Many of his series for 2000 AD were tied into the same continuity, under the umbrella of Indigo Prime. Indigo Prime was a multi-dimensional organisation that policed reality, recruiting recently dead people as its agents. The climax of the series was Killing Time, in which agents Winwood and Cord pursued a demon that had hitched a ride on a Victorian time machine, one of the legitimate passengers of which turned out to be Jack the Ripper.

Other series for 2000 AD include Revere, a post-apocalyptic occult story with artist Simon Harrison, which was reprinted in its entirety in the 2000 AD Extreme Edition title in February 2007, and Firekind (1993), an anthropological science fiction story involving alien cultures and dragons, illustrated by Paul Marshall. He has also written Rogue Trooper and Judge Dredd.

Examples of John Smith's cross-referencing of characters throughout his oeuvre include:

Renegade Indigo Prime agents Fervent and Lobe originally appeared in Tyranny Rex. Although Indigo Prime had only appeared in the Future Shock "A Change of Scenery" at that point, Smith said he always had the Smithiverse in mind: "They were both part of the same tailor-made Universe. That was intended right from the start."[3]

The character Mr Cheetl originally appeared in Firekind[5] and Mr Vathek, another member of his species the Chadarisq-Khan,[6] appears in Pussyfoot 5.[7]

Two members of Indigo Prime, Dazzler and Creed, appear in Scarab No. 7, "by that time I was probably just so sick of the thing I thought – 'Fuck it. I'll rip off my own story' – and stuck in 'Indigo Prime' as a lazy way out.".[3]

Winwood and Cord appear in the last few pages of Dead Eyes uploading Danny's soul into a cloned body after the human race in his place (Reality 377) are killed.[8]